Adenocarcinoma has become the most common histologic subtype of lung cancer in North America, and the proportion of lung cancers that are adenocarcinoma continues to rise. Although up to 90% of lung cancer is attributable to cigarette smoking, only 10-15% of smokers develop bronchogenic carcinoma in their lifetime. This observation, along with substantial literature implicating heritable polymorphic factors, indicates that other environmental and host factors influence individual susceptibility to tobacco smoke. This proposal will take advantage of an existing large case-control study of lung cancer and expand recruitment to focus specifically on the molecular epidemiologic analysis of lung adenocarcinoma risk. The role of a number of polymorphic xenobiotic metabolism enzymes involved in oxidative metabolism (Phase I), and the conjugation of reactive intermediates (Phase II) in lung adenocarcinoma risk will be examined, along with polymorphisms of genes involved with growth suppression, inflammatory and DNA repair pathways (Aim 1). Clinical, epidemiology and biologic information has suggested potential roles for gender factors, age, and environmental tobacco smoke (ETS) exposure in the specific development of adenocarcinoma of the lung, compared to other histologic subtypes. To address these gene-environment, gene-gender, gene-age, gene-ETS and gene-gene associations in lung adenocarcinomas, our proposal will build on our productive existing case-control study, with a goal to expand the age, gender, and possible ethnic diversity of our adenocarcinoma sample. Specifically, aim 2 will assess the role of gender and age with regard to genetic susceptibility to lung adenocarcinoma; and Aim 3 will assess the role of genetic polymorphisms among individuals reporting environmental tobacco smoke (ETS) exposure in susceptibility to lung adenocarcinoma. A better understanding of these risks will lead to improved preventive strategies. This proposal addresses directly a major research priority of the National Cancer Institute, specifically to identify genetic variations that affect cancer risk, often in concert with environmental factors.